US7153524B2 - Method for improving adsorption of a drug from ethylene oxide derivative - Google Patents

Method for improving adsorption of a drug from ethylene oxide derivative Download PDF

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US7153524B2
US7153524B2 US10/672,398 US67239803A US7153524B2 US 7153524 B2 US7153524 B2 US 7153524B2 US 67239803 A US67239803 A US 67239803A US 7153524 B2 US7153524 B2 US 7153524B2
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drug
ethylene oxide
compound
adsorption
macrogol
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US20050100607A1 (en
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Keiichi Yoshihara
Kazuhiro Sako
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Astellas Pharma Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus

Definitions

  • the present invention relates to a method for improving adsorption of a drug on the gastrointestinal mucous layers characterized in administration of a specific ethylene oxide derivative as the active ingredient for improving adsorption of a drug. Specifically, it relates to a method for improving adsorption of a drug on the gastrointestinal mucous layers characterized in administration as the active ingredient for improving adsorption of a drug one or more selected from polyethylene glycol, polyethylene oxide, and polyoxyethylene polypropylene copolymer where the average number of repeating oxyethylene units of one ethylene oxide chain length is 17 or greater.
  • H. pylori The existence of H. pylori was ascertained from the stomach tissues of gastritis patients and since that time, H. pylori has been shown to participate in the morbid state of stomach and duodenal disorders, including gastritis and peptic ulcer. There have been reports of the prevention of recurrence of ulcer associated with H. pylori, and the importance of the eradication of H. pylori is now recognized. It has further been suggested that there is a cause-effect correlation between the occurrence of stomach cancer and H. pylori infection, even in the absence of carcinogens ([non-patent reference 1]).
  • the ethylene oxide derivatives that are used as a base for formulation such as polyethylene glycol, polyethylene oxide, and polyoxyethylene polypropylene copolymer, are employed as solubilizing agents, plasticizers, dispersants, and stabilizers.
  • Polyethylene glycol is used, for instance, as a stabilizer of polypeptides, a plasticizer of sucralfate-containing compositions, and a base for retention [of a drug] in the blood.
  • polyethylene oxide is used as a base for controlling dissolution and polyoxyethylene polypropylene copolymer, for example, Pluronic, is used as a surfactant, solubilizer, emulsifier, dispersant, and the like.
  • the purpose of the present invention is to provide a method of improving adsorption of a drug on the gastrointestinal mucous layers from a specific ethylene oxide derivative.
  • Non-patent reference 2 Y. Akiyama et al., Drug Delivery System, 15-3; 185–192 (2000)
  • the present invention relates to
  • a method for improving adsorption of a drug on the gastrointestinal mucous layers characterized in that one or more selected from polyethylene glycol, polyethylene oxide, and polyoxyethylene polypropylene copolymer where the average number of repeating oxyethylene units of one ethylene oxide chain length is 17 or greater is administered as the active ingredient for improving adsorption of a drug;
  • the pharmaceutical composition according to above-mentioned 4 wherein the ratio of the components of the composition when the administration form is a solid is 0.01% to 95% of drug and 5% to 99.99% of ethylene oxide derivative per total composition and/or 0.1 mg to 1 g of drug and 50 mg to 1 g of ethylene oxide derivative.
  • gastrointestinal mucus means the adhesive secretion that is secreted from the gastrointestinal mucous membrane, for instance, the mucus at the stomach walls.
  • Gastrointestinal mucous layers refers to the layers of the above-mentioned gastrointestinal mucus that are formed on the surface of the gastrointestinal epithelial cells.
  • adsorption of a drug on the gastrointestinal mucous layers means in vitro adsorption of a drug on the gastrointestinal mucus components, reflecting in vivo adsorption of the drug.
  • lipid phase that is a component of gastrointestinal mucus and a drug suspension (aqueous phase) into contact with one another and then evaluate adsorption by determining the rate of adsorption of the drug on the lipid (refer to W. L. Agneta et al., Pharm. Res., 15; 66–71 (1998) on mucous layer composition). It appears that when adsorption is improved, “retention” in the gastrointestinal mucous layer is also improved, and there are cases in the present invention where “retention” is synonymous with adsorption.
  • “improvement of adsorption on the mucous layers” means that, for instance, the rate of adsorption of a drug on the oil phase when ethylene oxide derivative has been added to the aqueous phase is significantly increased in comparison to when ethylene oxide derivative is not added.
  • ethylene oxide derivatives are substances containing ethylene oxide chains in the molecules thereof, and examples are polyethylene glycol, polyethylene oxides, and polyoxyethylene polypropylene copolymer.
  • polyethylene glycol 6000 brand name Macrogol 6000, average relative molecular weight (hereafter average molecular weight) of 8000
  • polyethylene glycol 20000 brand name Macrogol 20000, average molecular weight of 20000
  • polyethylene oxides average molecular weight of 900,000 or 7,000,000
  • polyoxyethylene polypropylene copolymer brand name, Pluronic F68, Asahi Denka
  • the “average number of repeating oxyethylene units of one ethylene oxide chain length” means the number of repeating oxyethylene units per one ethylene oxide chain within a molecule as conveniently calculated. Specifically, this is found by calculating the value obtained by dividing the number of repeating oxyethylene units of all ethylene oxide chains contained in one molecule by the structural number of ethylene oxide chains.
  • the “structural number of ethylene oxide chains” means the number of ethylene oxide chains anywhere in the structure. For example, “the average number of repeating oxyethylene units of one ethylene oxide chain length” can be calculated as follows:
  • Pluronic has two ethylene oxide chains in its structure (Table 4) and therefore, the value obtained by dividing the total number of repeating oxyethylene units of ethylene oxide chains per molecule (n, Table 3) by two is “the average number of repeating oxyethylene units of one ethylene oxide chain length.” That is, the total number of repeating oxyethylene units of ethylene oxide chains molecules of L31, L44, L64, P103, P85, and F68 is 3, 20, 27, 29, 54, and 160, respectively; therefore, the “average number of repeating oxyethylene units of one ethylene oxide chain length” becomes 1.5, 10, 13.5, 14.5, 27, and 80, respectively.
  • Adsorption of a drug on the gastrointestinal mucous layers is improved when the “average number of repeating oxyethylene units of one ethylene oxide chain length” is 17 or greater, preferably 27 or greater.
  • antibiotics including nitroimidazole antibiotics, specifically tinidazole and metronidazole; tetracyclines, specifically tetracycline, minocycline, and doxycycline; penicillins, specifically amoxicillin, ampicillin, talampicillin, bacampicillin, lenampicillin, mezlocillin, and sultamicillin; cephalosporins, specifically cefaclor, cefadroxil, cephalexin, cefpodoxime proxetil, cefixime, cefdinir, ceftibuten, cefotiam hexetil, cefetamet pivoxil, and cefuroxime axetel; penems, specifically, faropenem and ritipenem
  • compositions that are used to treat disease associated with stomach acid secretion, and the like, such as acid pump inhibitors, specifically omeprazole and lansoprazole; and H2 antagonists, specifically, ranitidine, cimetidine, and famotidine.
  • acid pump inhibitors specifically omeprazole and lansoprazole
  • H2 antagonists specifically, ranitidine, cimetidine, and famotidine.
  • drugs used to treat hyponatremia specifically 4′-[2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl]carbonyl]-2-phenylbenzanilide hydrochloride; and antigastrin drugs, specifically (R)-1-[2,3-dihydro-1-(2′-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea, pirenzepine hydrochloride, secretin, and proglumide.
  • drugs used to treat hyponatremia specifically 4′-[2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl]carbonyl]-2-phenylbenzanilide hydrochloride
  • antigastrin drugs specifically (R)-1-[2,3-dihydro-1-(2′-methylphenacyl)-2
  • the ratio of each component when they are made into a composition.
  • the administration form when the administration form is a liquid, such as a suspension, there is 0.00005% to 50%, preferably 0.00015% to 0.25%, particularly 0.0003% to 0.15%, of drug per entire composition.
  • the administration form is a solid, such as a powder, it is possible to bring the amount of drug per entire composition to 0.01% to 95%, preferably 0.1% to 90%, of drug per entire composition, and to bring the amount of ethylene oxide derivative per entire composition to 5% to 99.99%, preferably 10% to 99.9%.
  • the administration form is a liquid
  • the amount of each component that is used when the administration form is a liquid, for instance, the amount of drug is brought to 1 mg to 1 g, preferably 0.5 mg to 750 mg, and the amount of ethylene oxide derivative is brought to 2 mg to 1 g, preferably 5 mg to 750 mg.
  • the amount of drug is brought to 0.1 mg to 1 g, preferably 0.5 mg to 750 mg, and the amount of ethylene oxide derivative is brought to 50 mg to 1 g, preferably 50 mg to 750 mg.
  • composition ratio there is a chance that sufficient adsorption of a drug will not be realized if the amount used is less than that cited here.
  • the ethylene oxide derivative of the present invention can be made into a pharmaceutical composition for oral use together with a drug and an appropriate filler and the like that are generally accepted pharmaceutically.
  • a pharmaceutical composition for oral use can take, and a form that can be orally administered, including powders, tablets, capsules, liquids, suspensions, and emulsions, can be cited as an example.
  • Formulation can be manufactured by a conventional production method.
  • Excipients such as fillers, disintegrators, binders, lubricants, fluidizing agents, dispersants, suspending agents, emulsifiers, preservatives, and stabilizers, can be included in the “filler and the like that are generally accepted pharmaceutically” as cited in the present invention.
  • fillers are lactose, mannitol, potato starch, wheat starch, rice starch, corn starch, and crystalline cellulose
  • examples of disintegrators are sodium bicarbonate and sodium lauryl sulfate
  • examples of dispersants are crystalline cellulose, dextrin, and citric acid
  • examples of solubilizing agents are hydroxypropyl methylcellulose, polyoxyethylene-hydrogenated castor oil, cyclodextrins, and polysorbate 80
  • examples of inflating agents are carboxymethyl cellulose, carboxymethyl cellulose calcium, and croscarmellose sodium
  • examples of surfactants are sodium lauryl sulfate and sucrose fatty acid ester.
  • One or two or more can be mixed in appropriate amounts as needed.
  • the manufacturing method when these are made into a pharmaceutical composition for oral use involves, for instance, introducing Macrogol 6000 (polyethylene glycol 6000), drug (compound A), and filler and the like as needed to a pharmaceutically acceptable medium and thoroughly mixing these until they are dissolved or suspended.
  • Macrogol 6000 polyethylene glycol 6000
  • drug compound A
  • filler and the like as needed to a pharmaceutically acceptable medium and thoroughly mixing these until they are dissolved or suspended.
  • Ion-exchanged water, buffer solution or physiological saline, and the like can be selected as the pharmaceutically acceptable medium.
  • this solution and/or suspension can be filled into capsules, such as gelatin capsules, to obtain a capsule form.
  • Macrogol 6000, compound A, and pharmaceutical filler and the like as needed are granulated by a conventional method, such as pulverizing, spray drying, freeze drying, wet granulation, or dry granulation, can be cited as a method of making a powder.
  • a conventional method such as pulverizing, spray drying, freeze drying, wet granulation, or dry granulation
  • FIG. 2 is a graph showing the effect of the total number of ethylene oxide (POE) repeating oxyethylene units per molecule on the rate of adsorption of a drug on the oil phase.
  • POE ethylene oxide
  • a specific amount of compound A was added to ion-exchanged water and a drug suspension was obtained by exposure for 20 minutes to ultrasonic waves (Sono Cleaner, Kaijo Corporation).
  • the concentration of polyethylene glycol 6000 (Sanyo Chemical Industries, Ltd.; brand name Macrogol 6000) added was adjusted to 0, 1.5%, 3.5%, 10%, 12%, and 35%.
  • the mucous layers in the digestive tract comprise water, mucin, proteins and lipids (W. L. Agneta et al., Pharm. Res., 15; 66–71 (1998)); thus, the effects of addition of Macrogol 6000 on solubility of compound A in various types of mucus components were investigated (Table 1).
  • solubility of compound A in aqueous mucin solution (sample (3), 5.9 ⁇ g/mL) was markedly increased when compared to solubility in water, when Macrogol 6000 was added (sample (4), 6.9 ⁇ g/mL), the increase was only 1.2-fold.
  • solubility of compound A in BSA solution as a model of a protein that comprises the mucous layers (sample (5), 18.0 ⁇ g/mL) was markedly increased when compared to solubility in water, when Macrogol 6000 was added (sample (6), 26.9 ⁇ g/mL), the increase was only 1.5-fold.
  • an in vitro test system wherein mixing of the oil components in the aqueous phase is prevented was constructed by immobilizing the oil phase with a gelling agent and separating it from the aqueous phase of a drug suspended in a mucin solution.
  • Immobilization of the oil phase was performed by adding 120 mg of an oil gelling agent, which is a natural oil and fat fatty acid extracted from castor oil (Johnson Co., Ltd.), to 2 mL of medium chain fatty acid triglyceride (Nihon Oils and Fats Co., Ltd.; brand name: Panaset) and preparing an oil gel in a test tube (inner diameter of 1 cm, Eiken tube No. 5).
  • the aqueous phase was recovered and compound A was assayed by HPLC. Furthermore, the surface of the oil phase was washed with methanol and compound A in the recovered solution was assayed by HPLC.
  • the rate of adsorption of a drug of compound A on the oil phase was measured by the same method as in Example 2.
  • In vivo anti- H. pylori activity was evaluated with animal experiments using Mongolian gerbil infection models.
  • the sample solutions were drug solutions that have been prepared by suspension of compound A using an 0.5% methylcellulose solution containing 0.2% of Macrogol 6000.
  • the drug was administered twice a day for three days at an administration volume of 20 mL/kg using an oral stomach tube.
  • the stomach was autopsied and excised and the number of H. pylori in the stomach were measured the day after the final administration.
  • In vivo anti- H. pylori activity was evaluated from clearance, that is, the ratio of the number of cases in which H. pylori was identified and the number of cases in which the number of bacteria after treatment was below the detection limit.
  • In vivo anti- H. pylori activity was evaluated by animal experiments using Mongolian gerbil infection models (Table 5).
  • the 0.5% methylcellulose suspension (MC suspension) showed clearance of 80% with a dose of 1 mg/kg.
  • MC suspension 0.5% methylcellulose suspension
  • clearance was 80% or greater with a dose of 0.1 mg/kg or higher, indicating that there was augmentation (10-fold) of the in vivo anti- H. pylori activity of compound A.
  • pylori activity of compound A appears to be that the Macrogol 6000 aggregated with the mucin so that the drug was taken up when the aggregate was adsorbed on the lipids (oils) that are mucus components, improving mucus adsorption of compound A (refer to Table 2).
  • Example 2 The amount of various drugs adsorbed in vitro was measured using the method in Example 2.
  • a solution of 600 ⁇ g of each compound suspended in 2 mL of an aqueous 0.8% mucin solution was prepared and brought into contact with the oil phase (n 3,6).
  • the aqueous phase was recovered and the drug content in the aqueous phase was found by assaying each compound with an ultraviolet-visible spectraphotometer.
  • the compounds that were used were nifedipin, nicardipine hydrochloride, compound B, and compound C.
  • Compound B was (R)-1-[2,3-dihydro-1-(2′-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea
  • compound C was 4′-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide hydrochloride.
  • the oil phase surface was washed with methanol and the drug adsorbed on the oil phase in the recovered solution was assayed with an ultraviolet-visible spectrophotometer for each compound.
  • the present invention relates to a method of increasing adsorption of a drug on the gastrointestinal mucous layers using an ethylene oxide derivative and makes it possible to augment the in vivo anti- H. pylori activity of a drug by increasing adsorption of a drug on gastrointestinal mucus. Furthermore, the present invention can be applied to singular drug eradication therapy, which has been difficult to accomplish by the current therapies for H. pylori eradication, and this will help to improve compliance.

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US20080166414A1 (en) * 2004-01-28 2008-07-10 Johns Hopkins University Drugs And Gene Carrier Particles That Rapidly Move Through Mucous Barriers
US20080213366A1 (en) * 2005-04-29 2008-09-04 Cubist Pharmaceuticals, Inc Therapeutic Compositions
US20100215580A1 (en) * 2006-09-08 2010-08-26 The Johns Hopkins University Compositions and methods for enhancing transport through mucus
US8544877B2 (en) 2010-12-30 2013-10-01 Autoliv Asp, Inc. Sloped faced airbag cushions for mitigating neck injury
US9056057B2 (en) 2012-05-03 2015-06-16 Kala Pharmaceuticals, Inc. Nanocrystals, compositions, and methods that aid particle transport in mucus
US9353123B2 (en) 2013-02-20 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9353122B2 (en) 2013-02-15 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9688688B2 (en) 2013-02-20 2017-06-27 Kala Pharmaceuticals, Inc. Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
US9790232B2 (en) 2013-11-01 2017-10-17 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US9827191B2 (en) 2012-05-03 2017-11-28 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US9890173B2 (en) 2013-11-01 2018-02-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10253036B2 (en) 2016-09-08 2019-04-09 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10336767B2 (en) 2016-09-08 2019-07-02 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10392399B2 (en) 2016-09-08 2019-08-27 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10688041B2 (en) 2012-05-03 2020-06-23 Kala Pharmaceuticals, Inc. Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus
US11219597B2 (en) 2012-05-03 2022-01-11 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications

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EP0645140B1 (en) 1993-08-31 1998-12-02 Takeda Chemical Industries, Ltd. Compositions for rectal administration containing benzimidazoles and fatty acid salts
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Cited By (52)

* Cited by examiner, † Cited by third party
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KR20050065550A (ko) 2005-06-29
JP4513007B2 (ja) 2010-07-28
MXPA05003162A (es) 2005-07-05
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CA2500218A1 (en) 2004-04-08
JPWO2004028567A1 (ja) 2006-01-19
CN1681534A (zh) 2005-10-12
AU2003268672A1 (en) 2004-04-19
US7816373B2 (en) 2010-10-19
US20050100607A1 (en) 2005-05-12
US20060204579A1 (en) 2006-09-14
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